Derangement of the blood clotting system contributes strongly to
multiple organ failure in
severe sepsis. In this review, we examine two microbial modulators of the clotting system:
polyphosphates and omptins.
Polyphosphates are linear
polymers of
inorganic phosphate that are abundant in the acidocalcisomes of prokaryotes and unicellular organisms as well as in the dense granules of human platelets.
Polyphosphates modulate haemostasis by: (1) triggering clotting via the contact pathway; (2) accelerating the activation of
coagulation factor V (a key cofactor in blood clotting) and (3) causing
fibrin to form clots whose fibrils are thicker and more resistant to fibrinolysis. While
polyphosphates are found in all prokaryotes, omptins have a more limited distribution among certain Gram-negative species. Omptins are outer membrane
aspartyl proteases which were recently found to proteolytically inactivate
tissue factor pathway inhibitor (
TFPI), the main inhibitor of the initiation phase of blood clotting.
Omptin activity against
TFPI requires
lipopolysaccharide without
O-antigen (rough LPS) such as is found on the surface of Yersinia pestis, the etiologic agent of
plague. Interestingly, expression of Pla, the Yersinia pestis
omptin, has a demonstrated virulence role in converting
plasminogen into the fibrinolytic
enzyme plasmin, which would seemingly antagonize any procoagulant effect of
TFPI inactivation. However, since the rate of
TFPI inactivation is much higher than the rate of
plasminogen activation, we suggest that Pla may have a dual function in supporting the bubonic form of
plague which is unique to Yersinia pestis.